Two new important studies on long COVID

Few victims are finding effective treatment for their symptoms

Dear readers:

If you have long COVID or are interested in it for other reasons, then these two new medical articles are worth you time. There is still no data on whether COVID vaccines may cause long COVID, and not just COVID infection.

Pathophysiology of Post-COVID syndromes: a new perspective

Abstract

Most COVID-19 patients recovered with low mortality; however, some patients experienced long-term symptoms described as “long-COVID” or “Post-COVID syndrome” (PCS). Patients may have persisting symptoms for weeks after acute SARS-CoV-2 infection, including dyspnea [shortness of breath], fatigue, myalgia [muscle pain], insomnia, cognitive and olfactory disorders. These symptoms may last for months in some patients. PCS may progress in association with the development of mast cell activation syndrome (MCAS), which is a distinct kind of mast cell activation disorder, characterized by hyper-activation of mast cells with inappropriate and excessive release of chemical mediators. COVID-19 survivors, mainly women, and patients with persistent severe fatigue for 10 weeks after recovery with a history of neuropsychiatric disorders are more prone to develop PCS. High D-dimer levels and blood urea nitrogen were observed to be risk factors associated with pulmonary dysfunction in COVID-19 survivors 3 months post-hospital discharge with the development of PCS. PCS has systemic manifestations that resolve with time with no further complications. However, the final outcomes of PCS are chiefly unknown. Persistence of inflammatory reactions, autoimmune mimicry, and reactivation of pathogens together with host microbiome alterations may contribute to the development of PCS. The deregulated release of inflammatory mediators in MCAS produces extraordinary symptoms in patients with PCS. The development of MCAS during the course of SARS-CoV-2 infection is correlated to COVID-19 severity and the development of PCS. Therefore, MCAS is treated by antihistamines, inhibition of synthesis of mediators, inhibition of mediator release, and inhibition of degranulation of mast cells.

Key summary points

• Post-COVID (PCS) syndrome may progress in association with the development of mast cell activation syndrome (MCAS).

• High D-dimer levels [an indication of blood clots] and blood urea nitrogen were observed to be risk factors associated with pulmonary dysfunction in COVID-19 survivors 3 months post-hospital discharge with the development of PCS.

• Persistence of inflammatory reactions, autoimmune mimicry, and reactivation of pathogens together with host microbiome alterations may contribute to the development of PCS.

• MCAS is treated by antihistamines, inhibition of synthesis of mediators, inhibition of mediator release, and inhibition of degranulation of mast cells.

Conclusions

PCS can develop within 3 months of acute COVID-19, but it can also develop after mild or asymptomatic COVID-19. The underlying pathophysiology of PCS is still unidentified, though immune dysregulation, persistence of inflammatory reactions, autoimmune mimicry, and reactivation of pathogens together with host microbiome alterations may contribute to the development of PCS. PCS may progress in association with the development of mast cell activation syndrome (MCAS). The emergence of MCAS during the course of SARS-CoV-2 infection is linked to the severity of COVID-19 and the emergence of PCS. Therefore, the use of antihistamines, inhibition of synthesis/release of mediators, and suppression of mast cell degranulation by anti-IgE may reduce MCAS-induced development of PCS. Perturbations of T cells in PCS could be mediated by histamine-dependent mechanisms, so antihistamines could be effective in the management of PCS. Taken together, the early recognition and treatment of MCAS in PCS patients may reduce systemic complications and long-term organ dysfunction.

Important statement:

“The final outcomes of PCS are chiefly unknown.”

Also:

“Famotidine [Pepcid] acts as an inverse agonist to inhibit the generation of cAMP or full antagonist to inhibit H2 receptors, thereby reducing endothelial permeability and endothelial dysfunction in Coved-19 [189]. Blocking of H2 receptors and induction of synthesis of cAMP by famotidine can decrease the pathological effects of histamine and mast cell cytokine release, respectively. Therefore, famotidine could be effective against SARS-CoV-2 infection in the acute phase and relieve symptoms of MCAS in patients with PCS.”

Outcomes among confirmed cases and a matched comparison group in the Long-COVID in Scotland study

Abstract

With increasing numbers infected by SARS-CoV-2, understanding long-COVID is essential to inform health and social care support. A Scottish population cohort of 33,281 laboratory-confirmed SARS-CoV-2 infections and 62,957 never-infected individuals were followed-up via 6, 12 and 18-month questionnaires and linkage to hospitalization and death records. Of the 31,486 symptomatic infections,1,856 (6%) had not recovered and 13,350 (42%) only partially. No recovery was associated with hospitalized infection, age, female sex, deprivation, respiratory disease, depression and multimorbidity. Previous symptomatic infection was associated with poorer quality of life, impairment across all daily activities and 24 persistent symptoms including breathlessness (OR 3.43, 95% CI 3.29–3.58), palpitations (OR 2.51, OR 2.36–2.66), chest pain (OR 2.09, 95% CI 1.96–2.23), and confusion (OR 2.92, 95% CI 2.78–3.07). Asymptomatic infection was not associated with adverse outcomes. Vaccination was associated with reduced risk of seven symptoms. Here we describe the nature of long-COVID and the factors associated with it.

In conclusion, 6–18 months following symptomatic SARS-CoV-2 infection, adults were at greater risk of a diverse group of symptoms, poorer quality of life and wide-ranging impairment of their daily activities, which could not be explained by confounding. Sequelae were more likely following severe infection and were not observed following asymptomatic infection and pre-infection vaccination may be protective. [emphasis added]

Comments on this study:

“It’s one more well-conducted, population-level study showing that we should be extremely concerned about the current numbers of acute infections,” said David Putrino, director of rehabilitation innovation for the Mount Sinai Health System in New York. “We are in trouble.” Among the issues that deserve more exploration is the degree of protection offered by vaccination, according to Putrino. Recent studies show that vaccination reduces the chance of developing long COVID, but not as much as previously thought. ‘’That is one of the most important things we need to understand next,’’ Putrino said.

Jill Pell, a professor of public health at the University of Glasgow who led the research, emphasized that the study revealed the wide-ranging impact of long covid on people’s lives. “There are lots of different impacts going beyond health to quality of life, employment, schooling and the ability to look after yourself,” she said. “Those who had covid were significantly more likely to get 24 of the 26 symptoms studied compared to the never-infected general population,” she said. For example, those who were infected were 3½ times more likely to be breathless.

Putrino pointed out that between 16 and 31 percent of the control group also suffered those same symptoms — a figure that is similar to the false negative rate of a PCR test, suggesting some of the control group may have been infected. Pell agreed that it is possible that some people with negative tests could have been infected, serving to reinforce the study’s broader findings.

‘’Crucially, this study also identified a sub-cohort of 11 percent who deteriorated over time. This is something seen often in patient groups but has not been discussed enough in the public conversation,’’ said Hannah Davis, a member of the Patient-Led Research Collaborative, a group of patients who have been engaged in long COVID research.